The long-term objective of this project is to develop, validate, and commercialize a novel rapid high-resolution 3D mapping system of the heart's electrical activity. Following performance and safety testing in large animals and humans, the system is envisioned to be used in the cardiac electrophysiology laboratory to generate patient-specific 3D maps of the heart's chambers that delineate both anatomical and electrical information. Such maps are used to guide the delivery of ablative energy with the goal of abolishing the clinical arrhythmia(s). This Phase I grant application specifically entails the construction of a prototype system and its initial validation in a bench-top setting. The incidence and prevalence of cardiac arrhythmias has seen explosive growth in the last few decades, mirroring an alarming increase in all forms of heart disease known to promote rhythm abnormalities. Atrial fibrillation alone has reached epidemic proportions, estimated to currently afflict ~2.3 million Americans and ~5.6 million by 2050. Traditional treatment modalities, namely drug therapy and open heart surgery, have been found to be inadequate for a growing number of patients, either because of poor efficacy, side effects, or the mere invasiveness of surgical procedures. The advent of specialized percutaneous catheters and the development of other enabling technologies have collectively led to an improvement in the safety and efficacy of minimally-invasive curative procedures. Having grown more than 10-fold in the last decade, percutaneous catheter-based procedures have become the preferred mode of intervention in symptomatic patients. Cardiac rhythm abnormalities present a major treatment challenge, as they are often selectively triggered and perpetuated by specific areas of the heart that tend to be highly variable between patients. Since most percutaneous procedures utilize an endocardial approach, effective therapy depends on reliable localization of the aberrant tissue on the complex endocardial surface and accurate delivery of ablative energy to culprit sites. In response to this emerging need, several systems have been developed to provide 3D anatomical and electrical mapping of cardiac chambers. Unfortunately, all available systems are plagued by significant limitations, particularly as they relate to mapping duration (sometimes exceeding an hour) and resolution. The potential consequences of slow and/or inaccurate mapping include the inability to map transient and hemodynamically unstable arrhythmias, unnecessary ablation of electrically normal cardiac tissue, repeat procedures for recurrence, and increased procedure and x-ray exposure times. Therefore, there is no doubt that rapid high-resolution mapping remains a significant unmet need in improving the outcome of curative catheter-based procedures. The proposed system would acquire intra-cardiac signals with a novel steerable multi-electrode array catheter across multiple beats and catheter locations. These data would then feed into a sophisticated computational algorithm to accurately reconstruct electro-anatomical information. The Rhythmia system constitutes next- generation technology uniquely architected to optimize the balance between mapping speed and resolution. The proposed methodology would allow complete coverage of a typical cardiac chamber in less than 60 seconds, producing electrical maps with the unprecedented resolution of 1-2mm. This combination of features would support the mapping of virtually all arrhythmogenic mechanisms, including VT (often characterized by intermittent runs and hemodynamic instability) and AF (for the validation of pulmonary vein isolation and mapping of underlying atypical flutters). By substantially shortening procedure times and enhancing mapping resolution, the Rhythmia system could have a profound impact on the quality of patient care and successfully compete with currently available 3D mapping systems. On the heels of previously performed feasibility studies, Phase I of the proposed project will include the development of a prototype system comprised of a proprietary computational engine running on a PC-based workstation, mapping catheter, and relevant hardware (amplifiers and filters). Once operational, the system would be tested and improved using a bench-top phantom model mimicking the electrical properties of blood and structures surrounding the heart. Specifically, Phase I will have the following aims: (1) Develop a prototype system that would be able to rapidly localize and visualize multiple sources of injected current within an ex vivo test chamber. (2) Quantify mapping spatial resolution ex vivo by localizing a single source of injected current. (3) Quantify overall mapping resolution ex vivo by localizing and timing an activation sequence simulated by sequential triggering of multiple sources of injected current. Feasibility will have been attained with the completion of Specific Aim #3, when the system demonstrates sub- 5mm error in localizing sources of injected current and sub-5ms error in determining activation times. Upon successful completion of bench-top validation, Phase II would be commenced comprising of large animal studies. PUBLIC HEALTH RELEVANCE: Cardiac rhythm abnormalities afflict a growing number of patients, with estimates ranging from 6 to 10 million people in the US alone. Minimally invasive procedures, such as catheter ablation, have established themselves as the preferred approach to eliminating cardiac arrhythmias and restoring normal heart beat. The proposed project looks to develop next-generation technology that would more rapidly and accurately localize the culprit tissue inside the heart. Superior mapping speed and accuracy would enable more targeted delivery of therapeutic ablative energy, thus improving both the safety and effectiveness of interventional procedures.